PIN1

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Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 is an enzyme that in humans is encoded by the PIN1 gene.[1][2]

Pin 1, or peptidyl-prolyl cis/trans isomerase (PPIase), isomerizes only phospho-Serine/Threonine-Proline motifs. The enzyme binds to a subset of proteins and thus plays a role as a post phosphorylation control in regulating protein function. Studies have shown that the deregulation of Pin1 may play a pivotal role in various diseases. Notably, the up-regulation of Pin1 is implicated in certain cancers, and the down-regulation of Pin1 is implicated in Alzheimer's disease. Inhibitors of Pin1 may have therapeutic implications for cancer[3][4] and immune disorders.[5]

Discovery

The gene encoding Pin1 was identified in 1996 as a result of a genetic/biochemical screen for proteins involved in mitotic regulation. It was found to be essential for cell division in some organisms. By 1999, however, it was apparent that Pin1 knockout mice had a surprisingly mild phenotype, indicating that the enzyme was not required for cell division per se. Further studies later found that loss of Pin1 in mice displays are not only neuronal degenerative phenotypes but also several abnormalities, similar to those of cyclin D1-null mice, suggesting the conformation changes mediated by Pin1 may be crucial for cell normal function.

Activation

Phosphorylation of Ser/Thr-Pro motifs in substrates is required for recognition by Pin1. Pin is a small protein at 18 kDa and does not have a nuclear localization or export signal. However, 2009, Lufei et al. reported that Pin1 has putative novel nuclear localization signal (NLS) and Pin1 interacts with importin α5 (KPNA1).[6] Substrate interactions and a WW domain determine subcellular distribution. Expression is induced by growth signals from E2F transcription factors. Expression levels fluctuate in normal, but not in cancerous cells. Expression is often associated with cell proliferation. Postranslational modifications such as phosphorylation on Ser16 inhibit the ability of Pin1 to bind substrate, and this inhibitory process may be altered during oncogenesis. It is hypothesized, but not proven, that Pin1 might also be regulated by proteolytic pathways.

Function

Pin1 activity regulates the outcome of proline-directed kinase (e.g. MAPK, CDK or GSK3) signalling and consequently regulates cell proliferation (in part through control of cyclin D1 levels and stability) and cell survival. The precise effects of Pin1 depend upon the system: Pin1 accelerates dephosphorylation of Cdc25 and Tau, but protects phosphorylated cyclin D from ubiquitination and proteolysis. Recent data also implicate Pin1 as playing an important role in immune responses, at least in part by increasing the stability of cytokine mRNAs by influencing the protein complexes to which they bind. Pin1 has been hypothesized to act as a molecular timer.[7]

Inhibition

PIN1 has been widely investigated as an interesting molecular target for the inhibition of cancer cell lines,[8][9] such as breast, cervical, ovarian, and endometrial cancers.[10] Studies have demonstrated that all-trans retinoic acid (ATRA), a natural compound derivative from Vitamin A is involved with PIN1 inhibition.[11] Furthermore, ATRA has also been reported to synergistically enhanced the ability of sorafenib to reduce Pin1 and inhibit cancer growth.[12] Some elemonic acid derivatives have also been reported with inhibitory activity against PIN1.[13] Some computational evidence has also demonstrated that some triterpenoids from neem could also inhibit PIN1 in a similar manner to elemonic acid derivatives[8]

Interactions

PIN1 has been shown to interact with:

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References

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  1. ^ Page Module:Citation/CS1/styles.css has no content.Lu KP, Hanes SD, Hunter T (Apr 1996). "A human peptidyl-prolyl isomerase essential for regulation of mitosis". Nature. 380 (6574): 544–7. Bibcode:1996Natur.380..544P. doi:10.1038/380544a0. PMID 8606777. S2CID 4258406.
  2. ^ Page Module:Citation/CS1/styles.css has no content."Entrez Gene: PIN1 Protein (peptidylprolyl cis/trans isomerase) NIMA-interacting 1".
  3. ^ Page Module:Citation/CS1/styles.css has no content.da Costa KS, Galúcio JM, de Jesus DA, Gomes GC, Lima e Lima AH, Taube PS, dos Santos AM, Lameira J (2019-10-25). "Targeting Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1: A Structure-based Virtual Screening Approach to Find Novel Inhibitors". Current Computer-Aided Drug Design. 15 (5): 605–617. doi:10.2174/1573409915666191025114009. PMID 31654518. S2CID 204907887.
  4. ^ Page Module:Citation/CS1/styles.css has no content.Campaner E, Rustighi A, Zannini A, Cristiani A, Piazza S, Ciani Y, Kalid O, Golan G, Baloglu E, Shacham S, Valsasina B (August 2017). "A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action". Nature Communications. 8 (1) 15772. Bibcode:2017NatCo...815772C. doi:10.1038/ncomms15772. ISSN 2041-1723. PMC 5472749. PMID 28598431.
  5. ^ Page Module:Citation/CS1/styles.css has no content.Rudrabhatla P, Albers W, Pant HC (2009-11-25). "Peptidyl-Prolyl Isomerase 1 Regulates Protein Phosphatase 2A-Mediated Topographic Phosphorylation of Neurofilament Proteins". Journal of Neuroscience. 29 (47): 14869–14880. doi:10.1523/JNEUROSCI.4469-09.2009. ISSN 0270-6474. PMC 3849796. PMID 19940183.
  6. ^ Page Module:Citation/CS1/styles.css has no content.Lufei C, Cao X (2009). "Nuclear import of Pin1 is mediated by a novel sequence in the PPIase domain". FEBS Letters. 583 (2): 271–276. Bibcode:2009FEBSL.583..271L. doi:10.1016/j.febslet.2008.12.011. PMID 19084525. S2CID 23995242.
  7. ^ Page Module:Citation/CS1/styles.css has no content.Lu KP, Finn G, Lee TH, Nicholson LK (Oct 2007). "Prolyl cis-trans isomerization as a molecular timer". Nature Chemical Biology. 3 (10): 619–29. Bibcode:2007NatCB...3..619L. doi:10.1038/nchembio.2007.35. PMID 17876319.
  8. ^ a b Page Module:Citation/CS1/styles.css has no content.da Costa KS, Galúcio JM, de Jesus DA, Gomes GC, Lima E, Lima AH, et al. (2020-11-09). "Targeting Peptidyl-prolyl Cis-trans Isomerase NIMA-interacting 1: A Structure-based Virtual Screening Approach to Find Novel Inhibitors". Current Computer-Aided Drug Design. 16 (5): 605–617. doi:10.2174/1573409915666191025114009. PMID 31654518. S2CID 204907887.
  9. ^ Page Module:Citation/CS1/styles.css has no content.Russo Spena C, De Stefano L, Poli G, Granchi C, El Boustani M, Ecca F, et al. (January 2019). "Virtual screening identifies a PIN1 inhibitor with possible antiovarian cancer effects". Journal of Cellular Physiology. 234 (9): 15708–15716. doi:10.1002/jcp.28224. hdl:10278/3711934. PMID 30697729. S2CID 59412053.
  10. ^ Page Module:Citation/CS1/styles.css has no content.Kim G, Bhattarai PY, Choi HS (February 2019). "Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 as a molecular target in breast cancer: a therapeutic perspective of gynecological cancer". Archives of Pharmacal Research. 42 (2): 128–139. doi:10.1007/s12272-019-01122-3. PMID 30684192. S2CID 59274466.
  11. ^ Page Module:Citation/CS1/styles.css has no content.Wei S, Kozono S, Kats L, Nechama M, Li W, Guarnerio J, et al. (May 2015). "Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer". Nature Medicine. 21 (5): 457–66. doi:10.1038/nm.3839. PMC 4425616. PMID 25849135.
  12. ^ Page Module:Citation/CS1/styles.css has no content.Zheng M, Xu H, Liao XH, Chen CP, Zhang AL, Lu W, et al. (May 2017). "Inhibition of the prolyl isomerase Pin1 enhances the ability of sorafenib to induce cell death and inhibit tumor growth in hepatocellular carcinoma". Oncotarget. 8 (18): 29771–29784. doi:10.18632/oncotarget.15967. PMC 5444702. PMID 28404959.
  13. ^ Page Module:Citation/CS1/styles.css has no content.Li X, Li L, Zhou Q, Zhang N, Zhang S, Zhao R, et al. (December 2014). "Synthesis of the novel elemonic acid derivatives as Pin1 inhibitors". Bioorganic & Medicinal Chemistry Letters. 24 (24): 5612–5615. doi:10.1016/j.bmcl.2014.10.087. PMID 25466185.
  14. ^ Page Module:Citation/CS1/styles.css has no content.Wulf GM, Ryo A, Wulf GG, Lee SW, Niu T, Petkova V, Lu KP (Jul 2001). "Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1". The EMBO Journal. 20 (13): 3459–72. doi:10.1093/emboj/20.13.3459. PMC 125530. PMID 11432833.
  15. ^ a b c d e Page Module:Citation/CS1/styles.css has no content.Shen M, Stukenberg PT, Kirschner MW, Lu KP (Mar 1998). "The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins". Genes & Development. 12 (5): 706–20. doi:10.1101/gad.12.5.706. PMC 316589. PMID 9499405.
  16. ^ Page Module:Citation/CS1/styles.css has no content.Goldstrohm AC, Albrecht TR, Suñé C, Bedford MT, Garcia-Blanco MA (Nov 2001). "The transcription elongation factor CA150 interacts with RNA polymerase II and the pre-mRNA splicing factor SF1". Molecular and Cellular Biology. 21 (22): 7617–28. doi:10.1128/MCB.21.22.7617-7628.2001. PMC 99933. PMID 11604498.
  17. ^ a b c Page Module:Citation/CS1/styles.css has no content.Lu PJ, Zhou XZ, Shen M, Lu KP (Feb 1999). "Function of WW domains as phosphoserine- or phosphothreonine-binding modules". Science. 283 (5406): 1325–8. Bibcode:1999Sci...283.1325L. doi:10.1126/science.283.5406.1325. PMID 10037602.
  18. ^ a b Page Module:Citation/CS1/styles.css has no content.Messenger MM, Saulnier RB, Gilchrist AD, Diamond P, Gorbsky GJ, Litchfield DW (Jun 2002). "Interactions between protein kinase CK2 and Pin1. Evidence for phosphorylation-dependent interactions". The Journal of Biological Chemistry. 277 (25): 23054–64. doi:10.1074/jbc.M200111200. PMID 11940573.
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  20. ^ Page Module:Citation/CS1/styles.css has no content.Ruan L, Torres CM, Qian J, Chen F, Mintz JD, Stepp DW, Fulton D, Venema RC (Feb 2011). "Pin1 prolyl isomerase regulates endothelial nitric oxide synthase". Arteriosclerosis, Thrombosis, and Vascular Biology. 31 (2): 392–8. doi:10.1161/ATVBAHA.110.213181. PMC 3075952. PMID 21051667.
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  22. ^ Page Module:Citation/CS1/styles.css has no content.Kamimoto T, Zama T, Aoki R, Muro Y, Hagiwara M (Oct 2001). "Identification of a novel kinesin-related protein, KRMP1, as a target for mitotic peptidyl-prolyl isomerase Pin1". The Journal of Biological Chemistry. 276 (40): 37520–8. doi:10.1074/jbc.M106207200. PMID 11470801.
  23. ^ Page Module:Citation/CS1/styles.css has no content.Wells NJ, Watanabe N, Tokusumi T, Jiang W, Verdecia MA, Hunter T (Oct 1999). "The C-terminal domain of the Cdc2 inhibitory kinase Myt1 interacts with Cdc2 complexes and is required for inhibition of G(2)/M progression". Journal of Cell Science. 112 (19): 3361–71. doi:10.1242/jcs.112.19.3361. PMID 10504341.
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  25. ^ Page Module:Citation/CS1/styles.css has no content.Wulf GM, Liou YC, Ryo A, Lee SW, Lu KP (Dec 2002). "Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage". The Journal of Biological Chemistry. 277 (50): 47976–9. doi:10.1074/jbc.C200538200. PMID 12388558.
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Further reading

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